Effect of combination therapy with fenofibrate and simvastatin on postprandial lipemia in the ACCORD lipid trial

Abstract

Objective: The Action to Control Cardiovascular Risk in Diabetes lipid study (ACCORD Lipid), which compared the effects of simvastatin plus fenofibrate (FENO-S) versus simvastatin plus placebo (PL-S) on cardiovascular disease outcomes, measured only fasting triglyceride (TG) levels. We examined the effects of FENO-S on postprandial (PP) lipid and lipoprotein levels in a subgroup of ACCORD Lipid subjects.

Research design and methods: We studied 139 subjects (mean age of 61 years, 40% female, and 76% Hispanic or black) in ACCORD Lipid, from a total 529 ACCORD Lipid subjects in the Northeast Clinical Network. PP plasma TG, apolipoprotein (apo)B48, and apoCIII were measured over 10 h after an oral fat load.

Results: The PP TG incremental area under the curve (IAUC) above fasting (median and interquartile range [mg/dL/h]) was 572 (352-907) in the FENO-S group versus 770 (429-1,420) in the PL-S group (P = 0.008). The PP apoB48 IAUC (mean ± SD [μg/mL/h]) was also reduced in the FENO-S versus the PL-S group (23.2 ± 16.3 vs. 35.2 ± 28.6; P = 0.008). Fasting TG levels on the day of study were correlated with PP TG IAUC (r = 0.73 for FENO-S and r = 0.62 for PL-S; each P < 0.001). However, the fibrate effect on PP TG IAUC was a constant percentage across the entire range of fasting TG levels, whereas PP apoB48 IAUC was only reduced when fasting TG levels were increased.

Conclusions: FENO-S lowered PP TG similarly in all participants compared with PL-S. However, levels of atherogenic apoB48 particles were reduced only in individuals with increased fasting levels of TG. These results may have implications for interpretation of the overall ACCORD Lipid trial, which suggested benefit from FENO-S only in dyslipidemic individuals.

Trial registration: ClinicalTrials.gov NCT00000620.

Figures

Figure 1

Postprandial incremental excursions for plasma TG, apoB48, and apoCIII. After fasting 12 h, participants had 0-h blood samples taken and then ingested a high-fat beverage containing 1,237 kcal/2 m2 body surface area from 75% fat (40% saturated, 20% monounsaturated, 15% polyunsaturated), 10% protein, and 15% carbohydrate. Sequential blood samples were obtained at 3, 5, 7, and 10 h after ingestion of the beverage. IAUC was calculated as described in research design and methods. The FENO-S group had a 30% reduction in plasma TG IAUC (A) and a 34% reduction in plasma apoB48 (B) compared with the PL-S group (statistical significance reported without adjustments). The IAUC for plasma apoCIII (C) was not different between the two groups.

Figure 2

Relationships between fasting plasma TG and the postprandial incremental excursions of plasma TG and apoB48. The fenofibrate effect on (log-transformed) IAUCs was analyzed by multiple regression with fenofibrate, sex, (log-transformed) day of study fasting TG, and fenofibrate × TG interaction as independent variables. For TG IAUC, the effect of fenofibrate was similar across the full range of day of study fasting TG (the solid and dashed regression lines are parallel) (A). The r value for the correlation between fasting TG and TG IAUC was 0.61 (P < 0.0001) for each group. In contrast, there was a significant interaction between day of study fasting TG levels and the effect of fenofibrate on the IAUC for apoB48 (the solid and dashed regression lines are not parallel) (B), whereby only participants with TG levels at and above the median had significant reductions in apoB48 IAUC (P = 0.003 for interaction; Table 2). Fasting TG and apoB48 IAUC were significantly correlated in the PL-S (r = 0.49; P < 0.001), whereas there was no significant relationship between fasting TG and apoB48 IAUC in the FENO-S group (r = 0.20; P = 0.11).